Lysine deacetylases (KDACs), more generally referred to as histone deactylases (HDACs), are a class of enzymes found in bacteria, fungi, plants and animals that catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins. These enzymes are implicated in a number of biological processes such as cell differentiation, proliferation, senescence, and apoptosis. Eighteen KDACs have been identified in the human genome. Eleven human KDACs are zinc-dependent enzymes; an additional seven KDACS use NAD as a cofactor. Zinc-dependent KDACs fall into three main classes, including class I (KDACs 1, 2, 3, and 8), class II, further subdivided into class IIa (KDACs 4, 5, 7, and 9) and class IIb (HDAC 6 and 10), and class IV (KDAC 11).
Aberrant KDAC activity is found in various disease states, most notably cancer, making these enzymes attractive targets for therapeutic intervention. The role of KDACs as epigenetic regulatory proteins has recently been reviewed (Falkenberg, Nat Rev Drug Discovery, 2014, 13: 673-691). To date, three KDAC inhibitors have been approved by the FDA for the treatment of cancer. These include vorinostat (Zolinza; Merck), approved for the treatment of cutaneous T cell lymphoma (CTCL), romidepsin (Istodax; Celgene), approved for the treatment of CTCL and peripheral T cell lymphoma (PTCL), and belinostat (Beleodaq; Spectrum Pharmaceuticals), approved for the treatment of PTCL.
To date, a number of small inhibitors of the zinc-dependent KDACs have been identified, including both natural products and synthetic compounds. These compounds have varying target specificity, pharmacokinetic properties and activity in laboratory and clinical settings. The most commonly used KDAC inhibitors target multiple KDACs, which makes it difficult to determine whether the biological consequences of KDAC inhibition, including clinical toxicities, are due to inhibition of a specific KDAC, the combined effect of inhibiting multiple KDACs and/or effects on one or more multiprotein complexes that incorporate specific KDACs as key enzymatic components
In general, the pharmacophore of KDAC inhibitors is composed of three regions: a “capping group”, which occludes the entrance of the active site pocket; a “zinc-binding group” (ZBG), which chelates the zinc ion in the active site and is required for catalytic function; and a “linker” which connects the capping group to the ZBG. The three core elements of the pharmacophore model are shown for KDAC inhibitor vorinostat below. Most KDAC inhibitors chelate the active site Zn using the hydroxamate moiety as a ZBG.

The most structurally complex capping groups are found in macrocyclic peptide and depsipeptide inhibitors (a depsipeptide inhibitor contains both amide and ester linkages). For example, largazole is a 16-membered ring macrocyclic depsipeptide isolated from the marine cyanobacterium Symploca sp. This natural product is a potent and class-1 selective KDAC inhibitor, with substantial potency against KDAC1, KDAC2, and KDAC3 in the picomolar range. It has been established that largazole acts as a prodrug, liberating the bioactive species largazole thiol, as shown below (Bowers, JACS, 2008, 130(33): 11219-22).

The modulation of pharmacokinetic and pharmacodynamic activity profiles of largazole-based KDAC inhibitors by employing different prodrug strategies to disguise the warhead has been reported. Others have attempted to improve specificity by varying the thiazole-thiazoline moiety in the capping group. In addition, Bowers et al. investigated the selectivity of fourteen peptide isosters analogs of largazole (Bowers, Org, Lett, 2009, 11(6): 1301-1304).
Currently, there are relatively few isoform-selective KDAC inhibitors available. Thus, there remains a need for structurally diverse KDAC inhibitors, particularly ones that are potent and/or selective inhibitors of KDAC classes and individual isoforms.